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Computer-Assisted Library Design (CALD)
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• Issues and Concepts in Combinatorial Library
  Design

• Size of the library
• Coverage of properties (chemical space)
• Diversity, Similarity, Redundancy
• Descriptor validation
• Subset selection from virtual libraries
• Analysis of Structure-Activity Relationships
  (SAR)

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Library Size Considerations
Generic library
Targeted/Biased library
Focussed library
Assay
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Example of target knowledge
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Coverage of properties (Chemical space
concept)
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What is similar?
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Different spaces, classified by
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16 diverse aldehydes...
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...sorted by common scaffold
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...sorted by functional groups
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• Key features in similarity/diversity
  calculations

• Properties to describe elements (descriptors)
• Distance measure (metric)

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Molecular Descriptors

• 1D Whole-molecule properties (e.g. molecular
  weight, melting point, logP etc.)
• 2D Presence or absence of molecular
  fragments - path-based -
  fragment-based - feature trees
• 3D - Surface properties (e.g. electrostatic
  potential, solvent accessible surface area
  etc.), - 3-dimensional shape, - Affinity
  fingerprints

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Path-based 2D fingerprints (implemented e.g. in
Daylight and Tripos software)
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Fragment-based 2D fingerprints (implemented e.g.
in MDL software)
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Feature Trees (Rarey and Dixon, J. Comp.-Aided
Mol. Des. 12 (1998) 471-490)
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in-vitro Affinity Fingerprints (Kauvar et al.,
ChemistryBiology, 2 (1995) 107-118)
Molecular similarity is defined by in-vitro
binding patterns ("Affinity Fingerprints") of a
ligand set (L) in reference binding assays (A)
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in-silico (virtual) Affinity Fingerprints (Briem
and Lessel, Perspect. in Drug Discovery Design,
20 (2000) 231-244)

• Terrapins in-vitro screening in diverse reference
  assays is simulated
• by Computational Docking into a reference panel
  of protein pockets (Docksim, Flexsim-X)
• by Computational Fitting onto a reference panel
  of small molecules (Flexsim-S)

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Some Distance Measures (Metrics)

• Tanimoto coefficient(only applicable for binary
  representations)

• Euclidian (geometric) distance(applicable for
  binary and non-binary representations)

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Calculation of Tanimoto coefficient
Bits set in Molecule A 4 Bits set in Molecule
B 4 Bits in common 3
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Calculation of Euclidian distance